title: IGF-1-mediated osteoblastic niche expansion enhances long-term hematopoietic stem cell engraftment after murine bone marrow transplantation.
abstract: The efficiency of hematopoietic stem cell (HSC) engraftment after bone marrow (BM) transplantation depends largely on the capacity of the marrow microenvironment to accept the transplanted cells. While radioablation of BM damages osteoblastic stem cell niches, little is known about their restoration and mechanisms governing their receptivity to engraft transplanted HSCs. We previously reported rapid restoration and profound expansion of the marrow endosteal microenvironment in response to marrow radioablation. Here, we show that this reorganization represents proliferation of mature endosteal osteoblasts which seem to arise from a small subset of high-proliferative, relatively radio-resistant endosteal cells. Multiple layers of osteoblasts form along the endosteal surface within 48 hours after total body irradiation, concomitant with a peak in marrow cytokine expression. This niche reorganization fosters homing of the transplanted hematopoietic cells to the host marrow space and engraftment of long-term-HSC. Inhibition of insulin-like growth factor (IGF)-1-receptor tyrosine kinase signaling abrogates endosteal osteoblast proliferation and donor HSC engraftment, suggesting that the cytokine IGF-1 is a crucial mediator of endosteal niche reorganization and consequently donor HSC engraftment. Further understanding of this novel mechanism of IGF-1-dependent osteoblastic niche expansion and HSC engraftment may yield clinical applications for improving engraftment efficiency after clinical HSC transplantation.
authors.affiliation: Department of Medical and Surgical Sciences of Children & Adults, University Hospital of Modena and Reggio Emilia, Modena, Italy; Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Caselli
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Olson
authors.forename: Satoru
authors.initials: S
authors.lastname: Otsuru
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Chen
authors.forename: Ted J
authors.initials: TJ
authors.lastname: Hofmann
authors.forename: Hyun-Duck
authors.initials: HD
authors.lastname: Nah
authors.forename: Giulia
authors.initials: G
authors.lastname: Grisendi
authors.forename: Paolo
authors.initials: P
authors.lastname: Paolucci
authors.forename: Massimo
authors.initials: M
authors.lastname: Dominici
authors.forename: Edwin M
authors.initials: EM
authors.lastname: Horwitz
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation / Q000379:methods*; D001842:Bone and Bones / Q000166:cytology; D002465:Cell Movement; D049109:Cell Proliferation; D006085:Graft Survival; D006410:Hematopoiesis; D018380:Hematopoietic Stem Cell Transplantation; D007334:Insulin-Like Growth Factor I / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010006:Osteoblasts / Q000502:physiology; D055153:Stem Cell Niche / Q000502:physiology*; D014916:Whole-Body Irradiation
chemical_list: D007334:Insulin-Like Growth Factor I
keywords: Insulin-like growth factor 1; Mouse; Niche; Osteoblasts; Stem cell transplantation